CN101679637B - Nontoxic polyethoxysiloxane material for the production of biologically resorbable and/or bioactive articles containing polyethoxysiloxane material, the production thereof, and the use thereof - Google Patents
Nontoxic polyethoxysiloxane material for the production of biologically resorbable and/or bioactive articles containing polyethoxysiloxane material, the production thereof, and the use thereof Download PDFInfo
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Abstract
The present invention relates to a polyethoxysiloxane (PES) material to be obtained in that (a) a first hydrolysis condensation reaction of a maximum of one group X of one or more different Si compounds of the formula (I) SiX4 (I) in which the groups X are the same or different and represent hydroxy, hydrogen, or ethoxy (EtO), are catalyzed in an acidic fashion at an initial pH value of 0 to <=7, is conducted in the presence of ethanol (EtOH) or an ethanol-water mixture as a solvent over a time period of 1 to 24 hours at a temperature of 0 DEG C to 78 DEG C, (b) a second hydrolysis condensation reaction of the material obtained in step (a) is conducted while simultaneously removing the solvent by successive evaporation in a gas diffusion-tight container at a pressure of 100 to 1013 mbar and a temperature of 50-78 DEG C until a drastic increase in viscosity to 0.5 to 2 Pa.s until a constant weight is attained and a cyclotetrasiloxane of the general formula ((SiO(OH)0,75(OEt)1,25 x 1/64 H2O)4 and a molar mass of approx. 456 g; (c) said PES material is cooled in a closed container over a time period from a few minutes to a few hours, and (d) the PES material obtained from step (c) is converted into an rPES material by a third hydrolysis condensation reaction.
Description
Technical field
The present invention relates to nontoxicity polyethoxye silicone compositions (PES material), is the polyethoxye silicone compositions (rPES material) of slaking when needing, and it is preferably formed with the form of one of multiple different polyethoxye silicone compositions (PES material).According to the present invention, this rPES material (r represents slaking) for example can be used as a kind of PES material and is spun into biology and can absorbs and/or bioactive fiber again; Further be processed into the fibrous reticulum as other PES materials then.The invention still further relates to that PES material, biology for the manufacture of slaking when needed can absorb again and/or the method for biological activity PES material, and the purposes of these materials.
Background technology
People pay multiple different effort to research and develop various biologies absorbing material more at present, and it is applied in the various uses of human medicine and medical technical elements, also are used for the other technologies field simultaneously, as filtering technique, biotechnology or insulation material industry.In addition, especially more and more higher for the requirement of the biological activity of material and toxicology properties in these fields.
The resorbable silicon polymer is known in the prior art.DE 196 09 551 C1 have described biodegradable and biological resorbable fibrous texture.These fibers can and carry out drying when needed and obtain in sol-gel method by oriented fibre from spinning component (Spinnmasse).This spinning component comprises one or more parts or all passes through the silicon compound of hydrolytic condensation, and these silicon compounds are from general formula SiX by the hydrolytic condensation method
4Monomer derived go out.The shortcoming of these fibers is and then degradeds after spinning process, does not show the optimum in cytotoxicity test, in some cases in addition must be rated for have cytotoxic.This toxicity definitely can not be accepted to be used in human medicine, medical technology, filtering technique, biotechnology or the insulation material industry, especially can not be used in wound healing or from the field of body fluid filtration cell.
In addition, the shortcoming of making manufacture method according to the fiber of DE 196 09 551 C1 is: in the hydrolytic condensation step, be multiphase mixture in removing the mixture that produces behind the solvent, must implement to filter to remove formed solid matter.Other liquid-state silicon polymkeric substance may have toxicity, but can't remove via filtration fully.In addition, particularly owing to formation and the enforceable filtration step of solid phase, lose the spinnable colloidal sols of vast scale.Also can between the maturation period, form the gellike phase of the more highly condensed silicon compound of suitable vast scale according to the method for DE 196 09 551 C1.This further reduces the ratio of spinnable colloidal sols composition.
Summary of the invention
The object of the present invention is to provide the nontoxicity biology again absorption and/or biological active materials, comprise the manufacture method of material and this non-toxic material of this material.
According to the present invention, biological activity refers to that the positive interaction between material and the tissue (for example wound tissue) causes the follow-up differentiation of tissue, and therefore organizes bonding or adhesion along interface between material and (recipient) tissue.
This purpose realizes that by colloidal sol according to the present invention or microemulsion (colloidal solution) it also is called the PES material according to the present invention.This microemulsion/colloidal solution obtains via following steps:
(a) maximum radicals X of one or more different formula I silicon compounds are implemented first hydrolysis-condensation reaction (HKR),
SiX
4 (I)，
Wherein, radicals X is identical or different, and representation hydroxy, hydrogen or oxyethyl group (EtO), exists ethanol (EtOH) or ethanol-water mixture as solvent, be under the temperature of 0 ℃ to 78 ℃ (boiling point of ethanol), to carry out acid catalysis under 0 to≤7 the situation in initial pH value, last 1 to 24 hour;
(b) in the container (rotary evaporator) of airtight and anti-gaseous diffusion, preferably reach at preferred 50 to 78 ℃ under the slight negative pressure of about 500mbar at the pressure of setting, more preferably from about evaporation continuously under 70 ℃ the temperature, the material that obtains in step (a) is implemented the 2nd HKR and removed solvent simultaneously, sharply rising to about 1Pas up to viscosity, is ((SiO (OH) until constant weight and formation general formula
0.75(OEt)
1.25* 1/64 H
2O)
4And molar mass is the cyclotetrasiloxane of the about 456g of 4 * about 114=;
(c) in container airtight, preferably anti-gaseous diffusion, to several hours, preferably in half an hour, cool off this PES material fast at several minutes; And
(d) will change into the rPES material by the PES material that step (c) obtains by the 3rd HKR.
It should be noted that to make according to nontoxicity biology of the present invention can absorb again and/or biological activity PES or rPES material that this manufacture method does not comprise maybe needn't comprise one or more filtration steps.This is the significant difference with DE 196 09 551 C1 disclosed methods.
When needed, step (d) can be carried out the 4th HKR as following steps (e1) to (e4) afterwards, thus can be by the PES material of the manufacturing of rPES material such as fiber (e1), powder (e2), block (e3) or the coating (e4) that obtain in the step (d).Therefore, these steps comprise following measure:
(e1) the rPES material being spun into biology can absorb and/or bioactive fiber again;
(e2) the materials processing powdered that will be obtained by step (d) as follows: the rPES material of gained is implemented dry, especially implemented lyophilized, and the rPES material of drying is pulverized (grinding) powdered;
(e3) will pour mould into and make it dry by the rPES material that step (d) obtains;
(e4) will be applied on the article to be coated by the rPES material that step (d) obtains, maybe these article be immersed in the rPES material.
The pH value of rPES material more preferably 5 to 7 in use, preferred 〉=6 especially, thus make the rPES material have acceptable (physiology) consistency.Be lower than at 5 o'clock at pH, material is because acidic nature and incompatible.Because in step (b), be evaporated to constant weight, namely up to not existing or having water hardly, so the strength of acid in the water-free system can not be defined as specific pH value.Usually should implement selectivity buffering (namely adding buffer reagent or the alkali that is fit to) or the reduction strength of acid of strength of acid in step (b) (for example passes through under the situation at nitric acid to discharge/evaporation NO
2), be 5 to 7 at the rPES material of step (e) back acquisition or the pH value of PES material when meeting water of moulding thus at last thereby make, especially 〉=6.
For this reason, preferably in step (b), reduce strength of acid, or the effect of buffering acid.But if this enforcement in step (b) perhaps is not implemented into preferred degree, then also can carry out in thereafter step (c) or (e), perhaps just and then carry out before applying PES material (for example on skin or wound).Yet, according to the present invention, particularly preferably in regulating correct strength of acid or acid effect in the step (b).
Especially can utilize the Tutofusin tris (Tris) of free alkali form or salt (for example triacetate, triphosphate) form, thereby reduce the acid effect in step (b), (c) or (e) or when the PES material is met water.
Set forth each step of described reaction in more detail below.
Step (a)
Tetraethoxysilane preferably used according to the invention (TEOS) is as the single silicon compound according to (first) of the present invention HKR Chinese style I.
For example use nitric acid (1N for example, the HNO of preferred 0.01N of dilution
3) to regulate initial pH value be 0 to≤7, is preferably 2 to 3.5.But, be suitable for the local NO of generation or NO
2All acidic mixtures and solution also be suitable in principle.For example can be also in having the physiological environment of molecular oxygen that (utilize nitricoxide synthase, Nitroxid-Synthase NOS) produces acidic mixture and the solution of nitrogen protoxide (NO) in the mode of enzyme, and the nitrogen protoxide that produces changes into NO fast by health again
2, perhaps also can be organic nitrate or nitric ether (so-called nitric oxide donors), for example the ethyl nitrate that forms by the organic nitrate reductase enzyme.Discharge NO in the mode of enzyme and need thiol group (halfcystine).
Therefore, according to the present invention, nitric acid except dilution, physiological compatibility acid (citric acid for example, succsinic acid, tartrate, acetic acid or xitix) and at least a indispensable amino acid (L-arginine for example, be preferably the L-Xie Ansuan, the L-leucine, the L-Isoleucine, the L-phenylalanine, Levothyroxinnatrium, the L-methionine(Met), L-Methionin (Lycin), the L-tryptophane) or non-essential amino acid (L-glutaminate for example, L-L-glutamic acid, altheine, the L-aspartic acid, the L-halfcystine, the L-glycine, the L-L-Ala, the L-proline(Pro), the L-Histidine, L-tyrosine) the aqueous solution or alcoholic solution (ethanolic soln of dilute with water more preferably) also are suitable as the substrate of NOS, to regulate the desired numerical value of pH in to slightly acidic to the moderate acid scope.
If use the nitric acid (for example 0.01N) of dilution to regulate pH, then its mol ratio at the silicon compound/nitric acid of formula (I) is preferably 110: 1 to 90: 1, is more preferably used under 100: 1 the situation.Advantageously at silicon compound (for example TEOS)/HNO of formula I
3Mol ratio be about under 100: 1 the situation and use nitric acid.
The preferred solvent that uses is ethanol-water mixture in step (a) according to the present invention, and its purpose is to dissolve or the silicon compound of emulsion formula I at least.If the silicon compound of formula I is TEOS, then water can't dissolve/silicon compound of emulsion formula I, therefore preferably sneaks into ethanol as solubilizing agent.The amount of ethanol is preferably 1 to 1.5mol/mol TEOS; According to a particularly preferred embodiment, the amount of ethanol is 1.26mol/mol TEOS.
Implement particularly preferred reaction batch as follows according to the present invention.In reaction vessel, be pre-loaded into the TEOS of 1mol, add the ethanol of 1.26mol then.Stir this mixture, thereby make dissolve with ethanol TEOS.Dilute the HNO of the 1N of 27.81g separately with the water of 60.38g
3(corresponding to the HNO of 1.75g
3) (total mass of the nitric acid of dilution is 88.19g, wherein H
2O accounts for 86.44g, corresponding to 4.8mol, and HNO
3Account for 1.75g, corresponding to 0.028mol; H
2O/HNO
3Mol ratio be 4.8/0.028=172.(thereby per 1 mole TEOS uses the H of 1.8mol then the nitric acid of the dilution of 33.07g to be added the ethanolic soln of TEOS
2The HNO of O and 0.01mol
3
The one HKR carries out in the mode of heat release.According to the present invention, be example with TEOS, a HKR means that hydrolysis takes place an oxyethyl group (EtO) in each TEOS molecule, and is continuing to make under the stirring OH base condensation of producing to carry out the dimerization effect and to decompose water outlet.In other words, under room temperature (RT), two kinds of solution (for example nitric acid of the TEOS in the ethanol and dilution) are converged, wherein at 2 SiX
4(namely for example 2 TEOS) generates X by hydrolysis and condensation by each oxyethyl group reaction
3Si-O-SiX
3(for example (EtO)
3-Si-O-Si-(EtO)
3) during, temperature rises to about 50 to 60 ℃.Initial temperature is unimportant in a HKR, because reaction is carried out with exotherm.Can be room temperature (RT), but also can be below or above room temperature, for example 5,10,15,20,35,45,60 or 70 ℃.Only must be enough high to carry out a HKR.
According to the present invention, especially preferably avoid each TEOS molecule hydrolysis more than an oxyethyl group.Therefore, for economic and practical reason, room temperature (about 20 ℃, when needing 18 to 25 ℃) is preferred.As long as in 0 ℃ to 78 ℃ scope, preferably in the scope of 10 ℃ to 70 ℃ or 20 ℃ to 60 ℃, the highest 78 ℃ higher temperature is fit to equally.Relation common in the chemistry is applicable to this temperature certainly, and lower temperature needs the longer reaction times, and vice versa.In an embodiment preferred of the present invention, a HKR lasts 1 to 12 hour, is preferably 5 to 8 hours.
Colloidal sol during churning is cooled to room temperature.If colloidal sol reaches room temperature and stops to stir, then must follow implementation step (b).Under the situation of implementation step (b) not, reaction mixture is should be not optionally at room temperature not static under condition of stirring not.Otherwise HKR can proceed, and mixture forms more highly condensed gel silicon compound.
The one HKR preferably carries out in mode in batches in the stirring-type container.Preferably be pre-loaded into silicon compound (for example TEOS) and the solvent (for example ethanol) of formula I.Add rapidly acid subsequently, preferably with the HNO of 0.01N
3(for example every mole of TEOS adds 0.01 mole HNO
3) form.Because the strength of acid in the reaction mixture, a HKR carries out rapidly, and the content in the container is heated to 50 ℃ to 60 ℃, and the temperature of (namely in step (a)) begins decline (owing to naturally cool to envrionment temperature, namely not having exterior cooling) between the reaction period then.
Step (b)
By 100 to 1013mbar, preferred 500 to 800mbar pressure and in room temperature to 70 ℃ is under preferred 60 to the 70 ℃ temperature of reaction, preferably with the slow consecutive evaporation under the situation of rotation of 20rpm in the container (rotary evaporator) of airtight and anti-gaseous diffusion
SimultaneouslyRemoving solvent (water, ethanol) and the material that obtains in step (a) is implemented the 2nd HKR, is ((SiO (OH) thereby form general formula
0.75(OEt)
1.25* 1/64 H
2O)
4And molar mass is the cyclotetrasiloxane of the about 456g of 4 * about 114g=, and viscosity sharply rises.
Must get rid of implementation step (b) under the situation of water, thereby can not continue to take place hydrolysis.Getting rid of water in this article refers to no longer continue from the outside to add water or do not have water to enter the reaction mixture via atmospheric moisture; Owing in condensation reaction, form water, and in step (a) optional adding water as solvent, so the reaction mixture in the step (b) is not moisture fully.
Vaporization temperature should not surpass 78 ℃ (boiling point of ethanol), otherwise solvent (mixture) can form bubble.Temperature is particularly preferably in more than 60 ℃, because acid under lower temperature, at HNO
3Situation under, NO
2The quantity not sufficient of evaporation, follow-up HKR carries out under the obvious stronger situation of acidity, finally residual higher acid concentration in material.
Understanding according to the present inventor, step (b) is that so-called reactive evaporation step especially preferably carries out rising to about 1Pas rapidly up to viscosity, and reach constant weight, up to cyclotetrasiloxane occurring, preferred simultaneously (by evaporative removal nitric acid or NO with supplementary mode
2) as far as possible further reduce strength of acid.Those skilled in the art can begin obviously to rise and reach 0.5 to 2Pas value and learn the end of step (b) from viscosity.
When the viscosity of reaction mixture is about 1Pas, preferably by being cooled to the temperature ending step (b) that is lower than 10 ℃, referring to following step (c).Have the microemulsion of single-phase " temperature " or the colloidal sol (PES material) of single-phase " temperature " then, it is 10s 4 ℃ and shearing rate
-1The time viscosity be 0.5 to 2Pas.
Allowing to remove water, ethanol and choosing wantonly and when using nitric acid, remove NO
2Temperature under implement reactive evaporation.70 ℃ is preferred on the viewpoint of practicality, but low slightly temperature, and for example 50 ℃ or 60 ℃ also is preferred.The present inventor by the support of initial experiment data, infers that the PES material (colloidal sol of the microemulsion of " temperature " or " temperature ") that obtains has ((SiO (OH) in step (b) under the situation that is not subjected to its Theory Thinking constraint
0.75(OC
2H
5)
1.25* 1/64 H
2O)
4Composition (MW=4 * 113.28g=453.12g), be the form of quadruple configuration, it has 4 Si-O unit, i.e. octatomic rings.
The attentive reader can find out, makes the further reaction and decomposite ethanol or water and subsequently with its removal of intermediate product of obtaining in (a) in step (b).If step (b) is not to carry out in airtight container, perhaps do not proceed to constant weight or viscosity and increase (preferably to 1Pas), then the inconsistent material of physiology can be stayed in the PES material, also can't or be difficult to remove in (e4) in step (c), (d) and/or (e1).
If in step (a), use the nitric acid of dilution as acid, then by making acid during the reactivity evaporation, resolve into NO
2, O
2And water, reduce thereby in step (b), implement possible preferred strength of acid.But (overwhelming majority) NO of discharge section only then
2(boiling point～21.2 ℃) only have (seldom) part to stay in microemulsion/colloidal sol.But if this system uses organic acid/arginine to replace nitric acid, then when acetic acid (can't discharge acid, for example) for example utilizes Tris solution raise pH value or reduction strength of acid when needed.
Find surprisingly that now keeping obtaining microemulsion at step (a) with (b) during described condition and remove solvent in step (b) after, its slaking in step (d) does not need filtration before, is single-phase.
Step (c)
This step is process of cooling, and its feature is that obviously the microemulsion of " temperature " that will obtain promptly in step (b), namely at several minutes in several hours, preferably in half an hour, be passed in the container airtight, preferably anti-gaseous diffusion, and be cooled to the temperature of implementation step (d).
Therefore, preferably be cooled to-20 ℃ to 10 ℃, more preferably 2 ℃ to 4 ℃, preferred especially 4 ℃ temperature.For example must avoid entering as atmospheric moisture or the moisture that is attached to the moisture on the container.In this step, also regulate material when needed, thereby the pH value that makes it after-applied material on article is 5 to 7, is preferably pH＞6.
Step (d)
Dynamically the slaking of control is the integral part of the inventive method, mainly just is implemented in the workability of the reaction mixture (PES material) of step (c) back acquisition in this step, but but for example is the form of spinnability or coating.In this step (d), implement the 3rd HKR, wherein be gathered into by the quadruple configuration (cyclotetrasiloxane) that will in step (b), produce and have 8 Siliciumatom and 12 general formula Si that are positioned at the oxo bridge on the rib that are positioned on the angle
8O
12(OH)
2(EtO)
6Cubes or cage (silicious sesquioxane), thereby improve the viscosity of reaction mixture.According to the viscosity that will reach, form the chain of cubes/cage or oligomerization silicious sesquioxane by silicious sesquioxane.
According to the present invention, implementation step (d) in container airtight, preferably anti-gaseous diffusion for example in so-called slaking beaker, is more preferably carried out in the already used container in step (c).Must avoid aqueous vapor or such as CO
2Other gases enter.According to the present invention, preferably-20 ℃ (more than) implementation step (d) to 10 ℃ the temperature, last 1 day to 4 weeks, more preferably implemented 3 to 18 days down at 2 ℃ to 4 ℃.Especially by in container airtight, preferably anti-gaseous diffusion under the condition of not shaking the depot reaction mixture, more preferably under 4 ℃, carry out slaking 3 to 5 days.But slaking equally can be preferably-20 ℃ (more than) carry out under the temperature to 10 ℃ the scope.
Those skilled in the art as can be known, temperature and reaction times are two amounts of being mutually related, and preferably regulate each other, thereby make the material of acquisition in step (c) change into general formula Si fully
8O
12(OH)
2(EtO)
6Silicious sesquioxane, and make so the rPES material that in step (d), obtains have dynamic viscosity, this is suitable for enforcement of step (e1) to one of (e4) and prepares for it.If material should be spun into fiber in step (e1), then the dynamic viscosity when step (d) finishes should be about 30 to 55Pas (4 ℃, shearing rate is 10s
-1), rate of loss is 3.5.Rate of loss is the elasticity of dynamic viscosity and the ratio of non-resilient component.Different therewith, if material should be processed into powder in step (e2), then the dynamic viscosity when step (d) finishes is about 60Pas (4 ℃, shearing rate is 10s
-1).If material is processed into block in step (e3), then the dynamic viscosity when step (d) finishes is preferably greater than and equals 70Pas (4 ℃, shearing rate is 10s
-1).If material is used for coated article or surface in step (e4), then depend on desired layer thickness, dynamic viscosity should (4 ℃, shearing rate be 10s smaller or equal to 10Pas
-1).
By the low temperature between the maturation period in the slaking beaker, from quadruple configuration (cyclotetrasiloxane), implement hydrolysis and the condensation (the 3rd HKR) of dynamically control, thereby form general formula Si
8O
12(OH)
2(EtO)
6Silicious sesquioxane.This silicious sesquioxane is assembled via hydrogen bridge band.
The present inventor is under the situation that is not subjected to its Theory Thinking constraint, support by the initial experiment data, infer that the rPES material that obtains in step (d) has following composition: between the accumulative phase, the 3rd HKR proceeds, thereby makes silicious sesquioxane (cubes) be gathered into general formula [OSi
8O
12(OH)
2(EtO)
5] oligomerization silicious sesquioxane (cubes chain), and be preferably formed one-dimensional chain.The oligomer structure of these cubes chain formation straight chains (accurate one dimension), it can easily reach 100 to 1000nm length.The cubes chain is all assembled mutually via hydrogen bridge, also comprises remaining oxyethyl group.
The chain-like structure of one dimension is expressed as the viscosity of particular form, i.e. so-called structural viscosity in macroscopic view.By increasing cubical HKR to form the cubes chain, further improve viscosity.Form the cubes chain at this, until desired viscosity.
Therefore, the final finished of carrying out slaking in the slaking beaker is the colloidal sol (rPES material) that can unrestrictedly preserve, and it has specific structural viscosity.Structural viscosity is a kind of fluid characteristics, under high shear shows lower viscosity; The shearing force that acts on the fluid is more big, and then viscosity (viscosity) is more low.The power on the oligomer in the colloidal sol of acting on causes the decline of viscosity, and this reactive force is used for making each colloidal sol particulate (being the oligomerization silicious sesquioxane at this) to arrange by orientation, and therefore can more preferably slip over each other; In addition, but especially about the size and dimension of the structure that realizes spinnability, referring to Sakka in Sol-Gel Technology for Thin Films, Fibers, Preforms, Electronics and Specialty Shapes, ed.L.C.Klein, Ncyes, Park Ridge, N.Y., 1988, the 140 pages and Fig. 2 .7.
According to the present invention, (basically) advantageously suppress the competitive three-dimensional polymer gel network that forms, the inventive method step (d) final finished afterwards be preferably comprise oligomerization silicious sesquioxane (cubes chain), the single-phase colloidal sol of hydrophobicity that do not contain the gel composition, that have oxyethyl group, its (basically) is not moisture, and is particularly suitable for standing storage, transportation and sale.
Because be step (d) in the slaking of not carrying out fully below-20 ℃ or dynamically control with minimum degree at most, so the PES material can unrestrictedly store under this temperature equally at step (c) under-20 ℃ " freezing " afterwards.This is a preferred scheme that changes, and is identical at situation and the rPES material after the step (d) that the preceding PES material of step (d) stores and transports.
The present inventor infers that the rPES material that obtains is general formula Si in step (d) under the situation of not accepting opinion thinking and the constraint of interim experimental data
8O
12(OH)
2(EtO)
6Silicious sesquioxane or consist of [OSi
8O
12(OH)
2(EtO)
5] the oligomerization silicious sesquioxane.
The title of silicious sesquioxane exists 1.5 times or the stoichiometric oxygen of sesquialter from each Siliciumatom.This type of compounds is known to be a series of geometries, particularly scalariform, cubes or cage structure.The silicious sesquioxane of condensation has [RSiO fully
1.5]
nStructure, be called polyhedron oligomerization silicious sesquioxane (POSS).Fully the POSS of condensation be known and commercially available in the document (Sigma-Aldrich company for example, St.Louis, MO, USA), it has a large amount of surrogates.Sigma-Aldrich company for example provides formula (CH
3)
8Si
8O
12Prestox-POSS and formula (C
5H
9)
7Si
8O
12(OH) cyclopentyl-POSS-silanol, both obviously are different from according to oligomerization silicious sesquioxane [OSi of the present invention
8O
12(OH)
2(EtO)
5].This type of five oxyethyl groups-POSS-silanol is not disclosed in the document yet (referring to http://www.sigmaaldrich.com/aldrich/brochure/al_chemfile_v1_no6 .pdf.
Known empirical formula RSiO also
1.5Silicious sesquioxane, wherein substituent R can be following group in theory: hydrogen, hydroxyl, alkyl, thiazolinyl, alkoxyl group and aryl.Silicious sesquioxane with following substituent R also is known in the document: methyl, propyl group, allyl group, methacryloyl, phenyl, hydrogen, hydroxyl.
Step (e1)
Under usual conditions, implement to be used for colloidal sol is processed into the spinning process of fiber, for example described in DE 19609551 C1 and DE 10 2,004 063 599 A1.The dynamic viscosity of colloidal sol is preferably 30 to 55Pas, and (4 ℃, shearing rate is 10s
-1), rate of loss is 3.5.In spinning process, rPES is blown out by the injector head with maximum 100 single nozzles via pressurized vessel, the pressure in the container is 1 to 100bar, is preferably 20bar.The fiber of Chan Shenging is usually by general formula [OSi at last
8O
12(OH)
2(EtO)
5] cubes chain (oligomerization silicious sesquioxane) form, it is laterally crosslinked each other in spinning process.The colloidal sol of discharging from (cold) nozzle experiences another (the 4th) HKR by (temperature) spinning pit shaft during dropping, this makes the jet of being discharged by nozzle form (stable) fiber by (molecule) of oligomerization silicious sesquioxane horizontal crosslinked reaction.The length of this spinning pit shaft is generally 1 to 5m, is preferably 2m.Weather in the spinning pit shaft is regulated in check mode aspect temperature and humidity, if need also can regulate the atmosphere that contains other reactants (for example ethyl nitrate) (atmospheric moistures of about 20 ℃ and about 35% (33 to 37%)).
Fiber is by after the tenesmus of spinning pit shaft, and cross section is circle rather than ellipse or dumb-bell shape, the profile that does not have corrugated to rise and fall in the vertical section, and have stable shape.Place it on the tables of traversing (Changiertisch).So the size of mesh of the non-fiber fabric that forms is controlled by the speed of traversing (Changiergeschwindigkeit).It is the cm/min of several units.Therefore, by before slowly and then produce the non-fiber fabric (fibrous reticulum) of narrow mesh, wherein also exist as siliceous initial compounds based on TEOS and surpass 30% oxyethyl group.
The fiber that makes in step (e1) according to the present invention is owing to the oxyethyl group that still exists has certain hydrophobicity.In addition, (basically) do not contain solvent (water, ethanol), and is particularly suitable for standing storage, transportation and sale.In fact a preferred embodiment of the present invention is, make fiber or fibrous reticulum according to step (e1), or make powder according to step (e2), (e3) with (e4), block and the article/surface through applying, and store, transport and sell according to embodiment of the present invention.
If in step (a), use the nitric acid of dilution as acid, then preferably under 30 ℃, remove the residual NO partly that comprises by exhaust
2(boiling point～21.2 ℃), thus realize that in step (e1), (e2), (e3) with (e4) possible preferred strength of acid reduces.But if this system uses organic acid/arginine to replace nitric acid, then when acetic acid (can't discharge acid, for example) for example utilizes Tris solution when needed, cleans in the Tris aqueous solution in the short period of time before applying, thereby rising pH value or reduction strength of acid.
Under the situation of (e4), obviously preferably store and transport with " freezing " state at step (c) back PES material.
Step (e2)
Before the drying or during, obtain dynamic viscosity by step (d) and be about 60Pas (4 ℃, shearing rate is 10s
-1) the rPES material, because its biological activity can be regarded as active substance, sneak into (other) active substance arbitrarily therein, effective substance on the pharmacology for example, perhaps by other, the 4th HKR take place the covalency bond (but below when using term " active substance ", generally do not refer to the rPES material from step (d), but other active substances).This preferably should carry out under the situation that produces uniform mixture.Especially under the situation of sneaking into the heat sensitivity active substance, behind the 4th HKR the mixture of being made up of PES material and active substance is implemented gently dried, for example spray is done or freeze-drying.If active substance does not have heat sensitivity or basic not interpolation, then can under the temperature that (obviously) improves, carry out drying.At this, preferably around active substance, form biology and can absorb again and/or biological activity matrix.This matrix especially also is suitable for enclosed liquid active substance (liquid can be enclosed in maintaining a long-term stability property in the matrix, and can in check mode discharges again).Seal machinery and the chemical stabilization of having realized active substance, realize the operability of the improvement of this liquid active substance and medicament, and help to prevent that active substance from volatilizing in uncontrolled mode.Certainly can in final molding (powder), there be other materials and/or the auxiliary agent that is suitable for various uses.For example http://www.photolagen.com/ has described the application of not using extra active substance, for example the addition material of skin cream etc.
This powder can be micropowder and/or nanometer powder.Be preferably 0.01 μ m to 100 μ m, more preferably 0.1 to 20 μ m according to micropowder particle grain size of the present invention (mean diameter).The particle diameter of nano-powder particles (mean diameter) usually≤100nm.
Step (e3)
In another embodiment, (before the drying or during) (when step (d) finishes, be 10s 4 ℃ of down cut speed from the rPES material of step (d)
-1The time dynamic viscosity be preferably greater than equal 70Pas) in sneak into (other) active substance, the covalency bond perhaps takes place by the 4th HKR in effective substance on the pharmacology for example.No matter whether there is (other) active substance subsequently, the rPES material is poured in the mould.Can obtain block in this way after the drying.This block can solid implant form as active substance transmission system (drug delivery system), for example subcutaneous medicament transmission system.It for example can be used as the storing chamber of contraceptive bian, and the long time of experience discharges active substance.This implant according to the present invention has good biocompatibility.The diameter of this block is preferred 〉=0.5mm.Optionally, this block also can be pulverized and grind into powder.
Step (e4)
But the slaking material from step (d) also can be processed into coating.For this reason, (4 ℃ of down cut speed are 10s by immersing the rPES material
-1The time dynamic viscosity smaller or equal to 10Pas) in, by with the cast of rPES material, perhaps by centrifugal coating or sprinkling rPES material, thereby apply article to be covered.Preferably on sugar-coat or capsule, the Powdered pharmaceutical mixture to compacting provides the biology of rPES material can absorb and/or the biological activity coating to coating again for this reason.Thus can be in prescription (for example by layer thickness and/or layer in proper order) control and/or control the release of (other) active substance.But this type of coating also can be applied on the implant of (for example being made of titanium) body portion, thereby improves (biology) consistency of implant, for example alleviates or avoids rejection.
According to another embodiment of the invention, available according to rPES material filling of the present invention or replacement high viscosity colloidal sol, especially hydrogel.High viscosity colloidal sol and hydrogel are used as the carrier of active substance or medicament in medicine and makeup.Hydrogel is widely used for the processing (wound treatment and wound healing) of big area wound usually.Preferably can improve biocompatibility by adding the rPES material, and therefore improve the healing state of wound.In this regard, can be advantageously used in the medicine according to hydrogel of the present invention, the biology in especially human medicine or the medical technology can absorb and/or bio-active products again.
The further processing of fiber and other application
This fiber can be used as fiber and fibrous reticulum as the finished product of one of preferable methods (comprising that step (a) to (d) reaches (e1)) according to the present invention.Also PES and rPES material equally have excellent biology absorptivity and/or biological activity again to these PES materials as described.These PES materials also are particularly suitable for standing storage, transportation and sale.
Before using this PES material, preferably for example can absorb again as the biology in human medicine or the medical technology and/or biological active materials (for example is used for wound treatment, wound healing, surgery sewing material or fortifying fibre at it; Also referring to next section) before and then, preferably with this PES material (fiber, powder, block, coating solution) immersion, more preferably in the slight outer immersion of depressing.Make the residual ethoxy complete hydrolysis that still exists by immersion, thereby make this material have stronger wetting ability.As mentioned above, can be (for example at phosphate buffered saline buffer H under the condition that pH raises
2PO
4 -/ HPO
4 2-In) soak, especially in step before, do not take place as yet under the situation of pH value rising.At this, implement the 5th and last HKR, remove still residual unhydrolysed oxyethyl group from the PES material simultaneously.
Another advantage is, compares with fiber and filamentary material that method according to DE 196 09 551 C1 obtains, and the PES that makes according to the present invention or rPES material and the material of forming thus demonstrate the numerical value of obvious improvement in the cytotoxicity test.This improvement is proved in the test that has L929-l cell (Mausfibroplasten).Therefore, the material that is obtained by step (e1) to (e4) according to the present invention is characterised in that good especially biocompatibility.
In the case, the biology that the fiber that makes according to the present invention or fibrous reticulum are advantageously used in human medicine, medical technology, filtering technique, biotechnology or the insulation material industry can absorb and/or biological active materials again.The material that makes according to the present invention especially can be advantageously used in the field of wound treatment and wound healing.Fiber for example can be used as surgery sewing material or fortifying fibre.Fibrous reticulum can be particularly advantageous for surface wound disposal, body fluid (for example blood) filtration or in the bio-reactor field, be used as and cultivate subsidiary (Anzuchthilfe).
Can load biologically active substance according to the present invention from step (e1), (e2), (e3) and PES material (e4), namely except comprising the biological activity silicon polymer, also comprise another kind of active substance, it can be delivered to real efficient part, perhaps influence the release of active substance on efficient part.Below these materials are called active substance carrier (drug delivery system).
Use is that according to slaking PES material of the present invention and according to the advantage of PES material of the present invention both process in a variety of ways, uses and combines with different (other) active substance.Particularly preferably, rPES material according to the present invention does not form reaction product with (other) active substance at this.PES material according to the present invention has biological resorbable and/or biological activity, and has the cytotoxicity values of improvement, and this helps to make material to have the biocompatibility of the improvement of lucky needs in medicine and medical technical field.
Set forth the present invention in more detail by following examples, but the present invention is not limited thereto.
Embodiment
All to be MCR 300 type viscometers of utilizing Physika company be 10s 4 ℃ and shearing rate to all viscosity that provide
-1Condition under record.
Embodiment 1: biology can absorb and/or biological activity rPES material (colloidal sol) and formation fiber and the fibroreticulate course of processing again
As the parent material of hydrolysis-condensation reaction, the TEOS (tetraethoxysilane) of 2.7mol (562.4g) is pre-loaded in the reaction vessel.Add the ethanol (156.8g) of 3.4 (2.7 * 1.26) mol as solvent.Stir this mixture.Use H separately
2The nitric acid (27.81g) of O (60.38g) dilution 1N.The nitric acid 89.28g that at room temperature will dilute subsequently adds whole TEOS-alcohol mixtures, thereby every mole of TEOS comprises the H of 1.8mol in the reaction mixture that produces
2The HNO of O and 0.01mol
3This mixture was stirred 5 hours.
Then by in the vacuum that applies 500mbar under 70 ℃ and slowly stir under the situation of (20rpm) and in rotary evaporator, evaporate (step (b)), thus the mixture that the step of making (a) back obtains moisture and ethanol hardly.Obviously reduce reduction form NO by this high temperature
2HNO
3The viscosity of this colloidal sol is about 1Pas, and (4 ℃, shearing rate is 10s
-1), significantly reduce strength of acid.
In step (c), with this solution in airtight polypropylene beaker (slaking beaker) at 30 minutes internal cooling to 4 ℃, and in step (d), in the slaking beaker, carrying out slaking 8 days under this temperature.Acquisition viscosity is about 40Pas, and (4 ℃, shearing rate is 10s
-1) the single-phase sol composition of homogeneous.This colloidal sol does not contain visible solid phase composition.
In step (e1), this colloidal sol is spun into fiber.Also be called spinning component or rPES material.Can in traditional spinning equipment, produce this fiber., spinning component is packed in the pressure roller that is cooled to-15 ℃ for this reason, it is applied the pressure of 20bar.Consequent power spinning by extruder composition passes through nozzle.Depend on nozzle diameter, the diameter of the spinning component of extruding (jet) is 50 to 100 μ m.To enter the length that is positioned at below the pressure roller be the spinning pit shaft of 2m to wandering honey shape jet because himself weight drops, and form the fiber of dimensionally stable in the reaction of this and atmospheric moisture, its cross section is circle rather than ellipse or dumb-bell shape, the profile that does not have corrugated to rise and fall.Regulate temperature and humidity in the spinning pit shaft in check mode.Temperature is 20 ℃, and atmospheric moisture is 35%.Form the fiber of dimensionally stable.This fiber still has slight reactivity in its surface.This fiber of inferring consist of [OSi
8O
12(OH)
2(EtO)
5] (oligomerization silicious sesquioxane).In the time of on impinging upon the tables of traversing, fiber is adhered each other on contact surface and is formed non-fiber fabric (fibrous reticulum).Subsequently that fibrous reticulum is air-dry under about 30 ℃ in loft drier, and further reduce the NO that comprises
2At this, reduce strength of acid to the degree of physical compatibility.
The fibrous reticulum that makes in embodiment 1 is according to ISO 10993-5 (1999); EN 30993-5 (1994) implements the cytotoxicity test.The value of trying to achieve with being used for contrast is compared, and the cytotoxicity of surveying shows that the fibrous reticulum that makes according to the present invention does not have the cytotoxin characteristic.
Comparative example
With parent material TEOS (tetraethoxysilane), ethanol, H
2O and HNO
3With mol ratio 1: 1.26: X: 0.01 (wherein, X=1.6,1.7,1.8,1.9 and 2.0) mixed, and powerful the stirring 5 hours at room temperature.In open containers, the solution of gained is suspended in the water-bath that adjusts the temperature to 70 ℃, and stays wherein until specific weight loss.Cooling subsequently, and use size of mesh to filter as the stainless steel mesh screen of 1mm * 1mm.Filtrate is depended on 6 hours to 6 months curing time of weight loss experience in encloses container under 3 ℃ temperature.
The spinning component that produces is very even, but and certain hour have stability and spinnability.Make fiber at dry-spinning equipment., spinning component is inserted in the spinning top that is cooled to-15 ℃ for this reason, and extruding and to make it at first be the stainless steel mesh screen of 80 * 80 μ m by size of mesh under 10 to 15bar pressure, be the nozzle of 100 μ m then by diameter.Be wrapped on the swing roller after the drying zone of the continuous fibre silk that produces through 1m.The fiber that produces depends on and batch namely adds the amount of water and have the shape of cross section that diameter is circle, ellipse or the dumb-bell shape of 5 μ m to 30 μ m.Cross-sectional area is 100 μ m
2To 400 μ m
2
Fiber surface is smooth, and does not have the profile that corrugated rises and falls fully.The tensile strength observed value of this fiber is 100MPa to 800MPa.The infrared spectra that obtains from this filamentary material is at 950cm
-1The place shows the Si-OH frequency band, at 3000cm
-1The place shows the C-H signal.The Ethoxysilane alcohol fiber that also has partial hydrolysis and part condensation.After at room temperature storing about 2 months, no longer demonstrate the C-H vibrating frequency band in the infrared spectra.This fiber is converted to the silanol fiber of part condensation, and it is gone through still has stability several moons.
The fiber that so makes is carried out the cytotoxicity test.The filamentary material that makes thus in the cytotoxicity test is according to ISO 10993-5 (1999); EN 30993-5 (1994) is identified has cytotoxic effect.
At this, only having in the entire reaction batch 50% can spinning.
Claims (26)
1. the polyethoxye silicone compositions that obtains by following steps:
(a) maximum radicals X of one or more different formula I silicon compounds are implemented first hydrolysis-condensation reaction,
SiX
4 （I），
Wherein, radicals X represents oxyethyl group, exists ethanol-water mixture as solvent, in initial pH value is to carry out acid catalysis under 0 to＜7 the situation under 0 ℃ to 78 ℃ temperature, lasts 1 to 24 hour;
(b) evaporation continuously under the temperature of 100 to 1013mbar pressure and 50 to 78 ℃ in the container of anti-gaseous diffusion is implemented second hydrolysis-condensation reaction to the material that obtains and is also removed solvent simultaneously in step (a), until being 10s 4 ℃ and shearing rate
-1Situation under viscosity sharply rise to 0.5 to 2Pas, until constant weight, and be (SiO (OH) until forming general formula
0.75(OC
2H
5)
1.25* 1/64H
2O)
4And molar mass is the cyclotetrasiloxane of 4 * 113.28g=453.12g;
(c) in airtight container, 2 minutes in 5 hours, the material that cooling is obtained by step (b); And
(d) will be changed into the polyethoxye silicone compositions of slaking by the material that step (c) obtains by the 3rd hydrolysis-condensation reaction.
2. according to the material of claim 1, it is characterized in that, is the slight negative pressure of 300mbar to 800mbar at the pressure described in the step (b).
3. according to the material of claim 1, it is characterized in that, is 70 ℃ in the temperature described in the step (b).
4. according to the material of claim 1, it is characterized in that, sharply rise to 1Pas in the viscosity described in the step (b).
5. according to the material of claim 1, it is characterized in that, is to prevent gaseous diffusion at the container described in the step (c).
6. according to the material of claim 1, it is characterized in that, in step (a), use the nitric acid of dilution or use by the acid of (i) physiological compatibility and (ii) acidic mixture or the solution adjusting pH value formed of the substrate of nitricoxide synthase be 0 to＜7.
7. according to the material of claim 6, it is characterized in that described physiological compatibility acid is citric acid, succsinic acid, tartrate, acetic acid or xitix.
8. according to the material of claim 6, it is characterized in that the substrate of described nitricoxide synthase is arginine.
9. according to the material of claim 6, it is characterized in that the nitric acid of described dilution is used under the situation of 90:1 to 110:1.
10. according to the material of claim 9, it is characterized in that the nitric acid of described dilution is used under the situation of 100:1.
11. the material according to claim 1 is characterized in that, passes through evaporation or volatilization NO in step (b)
2Perhaps utilize Tris solution to reduce strength of acid.
12. the material according to one of claim 1 to 11 is characterized in that, in step (c) with described material cooled Zhi 20 ℃ to+10 ℃ of –.
13. the material according to claim 12 is characterized in that, in step (c) with described material cooled to+2 ℃ to+4 ℃.
14. the material according to claim 12 is characterized in that, in step (c) with described material cooled Zhi 10 ℃ of – 20 ℃ Zhi –.
15. the material according to claim 12 is characterized in that, in step (c) with described material cooled to+4 ℃.
16. the material according to one of claim 1 to 11 is characterized in that, (carries out slaking under the temperature of 20 ℃ to 10 ℃ of Zai – among the d) in step.
17. the material according to claim 16 is characterized in that, carries out slaking in step (d) under 2 ℃ to 4 ℃ temperature.
18. the material according to claim 16 is characterized in that, carries out slaking in step (d) under 4 ℃ temperature.
19. the material according to one of claim 1 to 11 is characterized in that, implementation step (d) is 10s until described material 4 ℃ and shearing rate
-1Situation under viscosity be 30 to 55Pas.
20. the material according to claim 19 is characterized in that, implementation step (d) is 10s until described material 4 ℃ and shearing rate
-1Situation under viscosity be 40Pas.
21. the material according to one of claim 1 to 11 is characterized in that, in step (e1) the polyethoxye silicone compositions spinning of slaking being formed biology can absorb and/or bioactive fiber again.
22. the material according to claim 21 is characterized in that, the polyethoxye silicone compositions of slaking is processed into biology in other step (e2), (e3) or (e4) and can absorbs and/or bioactive powder, block or coating again.
23. the material according to claim 22 is characterized in that, in step (e1), (e2), (e3) or (e4) by evaporation or volatilization NO
2Perhaps utilize Tris solution to reduce strength of acid.
24. the material according to one of claim 1 to 11 is characterized in that, the silicon compound that uses in step (a) is tetraethoxysilane.
25. can absorb again for the manufacture of biology and/or the purposes of bioactive fiber, fibrous reticulum, powder, block or coating solution according to the material of one of claim 1 to 24.
26. according to the purposes of claim 25, wherein said fiber, fibrous reticulum, powder, block or coating solution be and then immersion before it uses.
Applications Claiming Priority (3)
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|---|---|---|---|
| DE102007026043.3 | 2007-06-04 | ||
| DE102007026043.3A DE102007026043B4 (en) | 2007-06-04 | 2007-06-04 | Non-toxic polyethoxysiloxane material for the manufacture of bioabsorbable and / or bioactive polyethoxysiloxane material containing articles, its preparation and use |
| PCT/DE2008/075002 WO2008148384A1 (en) | 2007-06-04 | 2008-06-03 | Nontoxic polyethoxysiloxane material for the production of biologically resorbable and/or bioactive articles containing polyethoxysiloxane material, the production thereof, and the use thereof |
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|---|---|
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| EP (1) | EP2152785B1 (en) |
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| BR (1) | BRPI0812581A2 (en) |
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| EP1602365A1 (en) * | 2004-03-03 | 2005-12-07 | Switch Biotech Aktiengesellschaft | Pharmaceutical composition for topical use in form of xerogels or films and methods for production |
| DE102007061874A1 (en) * | 2007-12-19 | 2009-06-25 | Bayer Innovation Gmbh | Non-toxic polysiloxane material for the manufacture of bioabsorbable and / or bioactive polysiloxane material-containing articles, their preparation and use |
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| WO1997045367A1 (en) * | 1996-05-29 | 1997-12-04 | Orion-Yhtymä Oy | Dissolvable oxides for biological applications |
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| CA2689211C (en) | 2016-02-23 |
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| EP2152785A1 (en) | 2010-02-17 |
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| PL2152785T3 (en) | 2012-10-31 |
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| WO2008148384A1 (en) | 2008-12-11 |
| RU2476455C2 (en) | 2013-02-27 |
| CN101679637A (en) | 2010-03-24 |
| AU2008258391A1 (en) | 2008-12-11 |
| CA2689211A1 (en) | 2008-12-11 |
| US8206675B2 (en) | 2012-06-26 |
| JP5617091B2 (en) | 2014-11-05 |
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